Placebo-Controlled Phase III Trial of Immunologic Therapy with Sipuleucel-T (APC8015) in Patients with Metastatic, Asymptomatic Hormone Refractory Prostate Cancer Eric J. Small, Paul F. Schellhammer, Celestia S. Higano, Charles H. Redfern, John J. Nemunaitis, Frank H. Valone, Suleman S. Verjee, Lori A. Jones, and Robert M. Hershberg A B S T R A C T Purpose Sipuleucel-T (APC8015) is an investigational immunotherapy product designed to stimulate T-cell immunity against prostatic acid phosphatase. A phase III study was undertaken to evaluate the safety and efficacy of sipuleucel-T in a placebo-controlled study. Patients and Methods A total of 127 patients with asymptomatic metastatic hormone refractory prostate cancer (HRPC) were randomly assigned in a 2:1 ratio to receive three infusions of sipuleucel-T (n = 82) or placebo (n = 45) every 2 weeks. On disease progression, placebo patients could receive APC8015F, a product made with frozen leukapheresis cells. Results Of the 127 patients, 115 patients had progressive disease at the time of data analysis, and all patients were followed for survival for 36 months. The median for time to disease progression (TTP) for sipuleucel-T was 11.7 weeks compared with 10.0 weeks for placebo (P = .052, log-rank; hazard ratio [HR], 1.45; 95%CI, 0.99 to 2.11). Median survival was 25.9 months for sipuleucel-T and 21.4 months for placebo (P = .01, log-rank; HR, 1.70; 95%CI, 1.13 to 2.56). Treatment remained a strong independent predictor of overall survival after adjusting for prognostic factors using a Cox multivariable regression model (P = .002, Wald test; HR, 2.12; 95%CI, 1.31 to 3.44). The median ratio of T-cell stimulation at 8 weeks to pretreatment was eight-fold higher in sipuleucel-T-treated patients (16.9 v 1.99; P  .001). Sipuleucel-T therapy was well tolerated. Conclusion While the improvement in the primary end point TTP did not achieve statistical significance, this study suggests that sipuleucel-T may provide a survival advantage to asymptomatic HRPC patients. Supportive studies are underway. J Clin Oncol 24:3089-3094. © 2006 by American Society of Clinical Oncology INTRODUCTION Prostate cancer is the most common malignancy in men, accounting for approximately 30,350 deaths in the United States in 2005. 1 Approximately 15% of men with prostate cancer present with metastatic disease, and 20% to 30% of men with localized dis- ease treated with definitive local therapy subse- quently develop metastatic disease. While the vast majority of patients with metastatic disease demon- strate a transient response to androgen deprivation, eventually all patients develop hormone refractory prostate cancer (HRPC) and virtually all prostate cancer deaths are due to the development of meta- static HRPC. 2 While docetaxel-based chemotherapy regimens have shown a modest survival advantage in HRPC patients, median survival remains approxi- mately 19 months, 3,4 and not all patients are candidates for chemotherapy. Novel agents and approaches are needed. One such approach involves the stimulation of prostate cancer specific T-cell immune responses. Sipuleucel-T is an investigational immuno- therapy product designed to stimulate T-cell immu- nity to prostatic acid phosphatase (PAP), an antigen expressed in the vast majority of prostate cancers but not in nonprostate tissue. Specifically, sipuleucel-T is composed of autologous antigen presenting cells (APCs) cultured with a fusion protein, termed PA2024, which consists of PAP linked to granulocyte- macrophage colony-stimulating factor. 5-7 PA2024 provides efficient loading and processing of antigen by APCs. 8 Data from phase I and II trials suggest that quiescent APCs cultured with PA2024 undergo activa- tion and upregulation of costimulatory molecules. 5 From the University of California San Francisco, San Francisco; Sharp Health- care, San Diego, CA; Eastern Virginia Medical School, Norfolk, VA; University of Washington; Dendreon Corporation, Seattle, WA; and the Mary Crowley Medical Research Center, Dallas, TX. Submitted October 7, 2005; accepted April 19, 2006. Supported by the Dendreon Corporation. Authors’ disclosures of potential con- flicts of interest and author contribu- tions are found at the end of this article. Address reprint requests to Eric J. Small, MD, UCSF Comprehensive Cancer Center, University of California, San Francisco, 1600 Divisadero St, Box 1711, San Francisco, CA 94115; e-mail: smalle@medicine.ucsf.edu. © 2006 by American Society of Clinical Oncology 0732-183X/06/2419-3089/$20.00 DOI: 10.1200/JCO.2005.04.5252 JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T VOLUME 24  NUMBER 19  JULY 1 2006 3089 Downloaded from ascopubs.org by 3.88.16.191 on June 9, 2022 from 003.088.016.191 Copyright © 2022 American Society of Clinical Oncology. All rights reserved.